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Canadian-led team links gene to Alzheimer's

By Joseph HallHEALTH REPORTER

Mon., Jan. 15, 2007

An international team of scientists, spearheaded by University of Toronto researchers, has discovered a gene responsible for many cases of the most common form of Alzheimer's disease. The gene can cause late onset Alzheimer's in large numbers of seniors and crosses ethnic and racial lines.

"What we found is this gene is robustly associated with increased risk for common forms of late onset Alzheimer's disease in several different ethnic groups," says Dr. Peter St. George-Hyslop, head of the Centre for Research in Neurodegenerative Disease at the U of T.

"It's likely to be a significant contributor to the causes of Alzheimer's disease. It's probably a significant player in this (ailment)."

St. George-Hyslop said it is too early to say with any certainty how many of those who carry the defective form of the gene – known as SORL1 – will eventually suffer from Alzheimer's.

But he did estimate that roughly 60 per cent of people who have the mutant gene may contract the disease.

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"However, regardless of how frequent and how powerful SORL1 variants turn out to be, any knowledge in a disease like Alzheimer's is still incredibly important," he says.

"Each new piece of the puzzle helps solve the overall puzzle faster and brings new opportunities for imaginative new approaches to diagnosis and treatment."

St. George-Hyslop could not say how common the mutant gene might be in the population or how many people with Alzheimer's might have it.

But he says those who carry the mutated gene have between a 1.2 to two-fold increase in their risk of contracting Alzheimer's, compared to people with the normal variety.

The study, which will appear in the February issue of the journal Nature Genetics, was published online yesterday.

It also included lead research from the Columbia University Medical Centre and the Boston University School of Medicine.

About 90 per cent of all Alzheimer's cases are of the late onset variety.

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Typically, this form of the disease afflicts people from about 65 years and up.

St. George-Hyslop says the normal form of the SORL1 gene creates a protein that acts like an inter-cellular transit vehicle, transporting a substance known as APP to safe regions of healthy brain neurons.

The crippled version of SORL1, however, cannot perform this transit function, allowing APP to enter "forbidden regions" of brain cells where it is broken down into a neurotoxin known as amyloid beta peptide.

Amyloid beta peptides – or Abeta for short – are believed to begin a cascading chain of brain cell degeneration that leads to Alzheimer's.

"We believe the genetic defects are likely to impede the function of SORL1, resulting in more APP being sent to places in the cell where it's degraded into Abeta peptide," St. George-Hyslop says.

Abeta produces the signature clumps of toxic plaque that pepper the brains of Alzheimer's patients.

St. George-Hyslop is considered to be one of the world's top Alzheimer's researchers. In a study published last April, he identified a naturally occurring brain chemical that stopped the production of Abeta in neuron cells.

The current study looked at DNA samples from 6,000 volunteers – some with and some without Alzheimer's. These volunteers came from four different ethnic groups, including Northern Europeans, African-Americans, Caribbean-Hispanics and a group of Arabs living in a small community in northern Israel.

Most previous Alzheimer's studies have concentrated on whites of European ancestry.

Many study volunteers were selected from families where at least two members were living with Alzheimer's disease, says study co-author Dr. Richard Mayeux, of Columbia's Taub Institute for Research on Alzheimer's Disease and the Aging Brain.

As well, Mayeux says, a large data-set from autopsies of Alzheimer's patients was used.

There was also a control group of healthy volunteers used for comparison purposes.

The gene is the second discovered that has been associated with late onset Alzheimer's. The first, known as ApoE4, was identified in 1993.

Like the earlier discovery, which also carries about a 60 per cent risk factor for the disease, SORL1 does not afflict everyone who carries it with Alzheimer's.

As with almost all cases of late onset Alzheimer's, there are critical environmental factors at play in bringing on the ailment.

Such things as diabetes, high blood pressure, brain traumas and even education levels are known to be crucial factors in the development of the disease and likely interact with genetic predispositions in its onset.

St. George-Hyslop says future work will be needed to pinpoint the exact regions of the SORL1 gene responsible for kicking off the Alzheimer's process.

"We do think that there are likely to be at least two, or possibly more different mutations (of SORL1) that are capable of causing the disease," he said.

Identifying these mutations could lead to the creation of medicinal therapies that would fix or replicate the function of the disabled gene, St. George-Hyslop says.

And such knowledge could be used to identify people in danger of having Alzheimer's, allowing existing and future preventative therapies to be used.

Dr. Jack Diamond, scientific director of the Alzheimer's Society of Canada, called the study "good and exciting", while cautioning it was only one part of a huge Alzheimer's puzzle.

Diamond says the gene gives researchers a "solid place to start" in seeking the mechanisms at play in the disease, and at where critical environmental factors might be involved in the disease process.

"It's something, it's a start. And if you've got somewhere to start that takes away some of the mystery. You never know how quickly science develops."

Nancy MacArthur, president of the Alzheimer's Society of Ontario, says the discovery and other findings give "us hope that something will be done".

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